Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

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Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-

Component Assembly, Peroxide-Preserving Rearrangement, and

Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

Ivan A. Yaremenko,* Yulia Yu. Belyakova, Peter S. Radulov, Roman A. Novikov, Michael G. Medvedev,

Nikolai V. Krivoshchapov, Alexander A. Korlyukov, Igor V. Alabugin,* and Alexander O. Terent ’ev *

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ABSTRACT: Stable bridged azaozonides can be selectively assembled via a catalyst-free

three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group

source such as aqueous ammonia or ammonium salts. This procedure is scalable and can

produce gram quantities of bicyclic stereochemically rich heterocycles. The new

azaozonides are thermally stable and can be stored at room temperature for several

months without decomposition and for at least 1 year at −10 °C. The chemical stability

of azaozonides was explored for their subsequent selective transformations including the

ﬁrst example of an aminoperoxide rearrangement that preserves the peroxide group. The

amino group in aminoperoxides has remarkably low nucleophilicity and does not

participate in the usual amine alkylation and acylation reactions. These observations and

the 15 pK_aunits decrease in basicity in comparison with a typical dialkyl amine are

attributed to the strong hyperconjugative n_N→σ*_C−Ointeraction with the two

antiperiplanar C−O bonds. Due to the weakness of the complementary n_O→σ*_C−N

donation from the peroxide oxygens (a consequence of “inverse α-eﬀect”), this interaction depletes electron density from the NH

moiety, protects it from oxidation, and makes it similar in properties to an amide.

these molecules is illustrated by the fact that their ﬁrst total

synthesis was developed only in 2015 by Baran’s group.⁸⁴

The few known “unnatural” amino peroxides reveal

promising biological activity. For example, 11-aza-artemisinin,

i.e., the product of replacement of the ester moiety of

artemisinin with an amide group, is more potent against

malaria than artemisinin itself.⁸⁵⁻⁸⁷Furthermore, both 11-aza-

artemisinin and 6-aza-artemisinin exhibit anticancer activ-

ity.⁸⁸⁻⁹⁰

Hence, the development of stable and easily accessible cyclic

peroxides fused to a nitrogen heterocycle remains an important

problem. Although the introduction of a nitrogen atoms can

dramatically expand the choices of possible peroxide-

containing functionalities and strongly aﬀect their interaction

with biological targets, the lack of available synthetic

approaches and intrinsic instability left azaperoxides in the

shadow of artemisinin and other classic peroxides.

INTRODUCTION

■

Organic peroxides oﬀer a largely uncharted chemical space for

the development of new medicinal agents with antimalarial,¹⁻⁹

anthelmintic,¹⁰⁻¹⁵anticancer,¹⁶⁻²⁶fungicidal,^26,27antitubercu-

lar,²⁸⁻³⁰and antiviral³¹⁻³³activities. Artemisinin, a natural

peroxide recognized by the 2015 Nobel Prize in Medicine to

Youyou Tu, and its synthetic analogues such as arterolane are

important antimalarial drugs. Furthermore, both artemisinin

and the ethanolic extract of Artemisia annua L. are highly

potent at inhibiting the proliﬁerating ability of SARS-CoV-2

(the COVID-19-causing virus).³⁴⁻³⁶

The dramatic expansion of medicinal chemistry of organic

peroxides was inspired by >100 known peroxide-containing

natural products.³⁷⁻³⁹The variety of natural examples lessened

concerns associated with the perceived peroxide instability and

led to research eﬀorts aimed at the development of synthetic

approaches to varied classes of cyclic peroxides including 1,2-

dioxolanes,⁴⁰⁻⁵⁰1,2,4-trioxolanes (ozonides),^26,51−581,2-diox-

anes,⁵⁹⁻⁶⁴1,2,4-trioxanes,⁶⁵⁻⁶⁹1,2,4,5-tetraoxanes,⁷⁰⁻⁷²cyclic

triperoxides,⁷³and tricyclic mono- and bisperoxides.⁷⁴⁻⁷⁶

However, notwithstanding the signiﬁcant advances in the

medical chemistry of peroxides, azaperoxides remain mostly

unexplored. Only two natural azaperoxides, verruculogen⁷⁷⁻⁸¹

and fumitremorgin A,^82,83are known (isolated from Aspergillus

fumigatus in the 1970s, Figure 1). The challenging nature of

Received: February 27, 2021

Published: April 20, 2021

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In this study, we resurrect peroxidative three-component co-

condensations of ketones as a preparative approach to peroxy

N-heterocycles and describe a convenient approach to the

selective assembling of stable bridged azaozonides via a

condensation of 1,5-diketones with hydrogen peroxide and

an NH-group source. We also report that the new azaperoxides

are suﬃciently stable to participate in a variety of further

chemical transformations including the ﬁrst example of an

azaperoxide rearrangement that preserves the peroxide group.

RESULTS AND DISCUSSION

■

Three-Component Condensation of 1,5-Diketones

with Hydrogen Peroxide and NH-Group Source with

the Formation of Bridged 1,2,4-Dioxazolidines (Bridged

Azaozonides). The catalyst-free three-component condensa-

tion of 1,5-diketones 1a−u with hydrogen peroxide and an

NH-group source can be accomplished with aqueous H₂O₂

and a variety of NH-group sources such as aqueous NH₃,

ammonium acetate, ammonium formate, and ammonium

carbonate. In all cases bridged 1,2,4-dioxazolidines (bridged

azaozonides) 2a−u and 3a−r are formed (Scheme 1 and

Scheme 2). Unlike two-component condensation of 1,5-

diketones with hydrogen peroxide, Lewis acid catalysis is not

necessary.

Figure 1. Structures of artemisinin and bioactive azaperoxides.

The main expected reason for the instability of azaperoxides

is their self-oxidation due to the presence of both an oxidizing

and a reducing part in the molecule. Oxidation of amines with

hydrogen peroxide is well known and used for the synthesis of

nitroso and nitro derivatives,^91,92nitrones/N-oxides,⁹³⁻⁹⁵and

imines.^96,97

Condensation of ethyl 2-acetyl-2-(4-chlorobenzyl)-5-oxo-

hexanoate (1l) with a nitrogen source and hydrogen peroxide

was used to study the eﬀect of the nature and amount of the N-

component, hydrogen peroxide, solvent, and reaction time on

the yield of stereoisomeric bridged azaozonides 2l and 3l

(Table 1; for additional experiments see Table S1 in the

Supporting Information). A preliminary procedure for

condensation of diketone 1l with H₂O₂and an NH-group

source was as follows: an NH₃source and aqueous H₂O₂were

added to a solution of the diketone 1l (0.300 g; 0.92 mmol) in

a solvent at room temperature. After completion, the solvent,

an excess of ammonia, and hydrogen peroxide were removed in

a vacuum of a membrane pump at 40−50 °C.

The instability of aminoperoxides and the diﬃculty of their

isolation and puriﬁcation impose signiﬁcant limitations on the

development of methods for their synthesis. The ﬁrst attempts

to synthesize azaperoxides from highly reactive acyclic

monoketones, aldehydes, and small ring size cyclic ketones

were reported by E. G. E. Hawkins⁹⁸⁻¹⁰⁰in the 1970s. The

yields of aminoperoxides did not exceed 40%. In addition,

attempts have been made to synthesize azaperoxides by other

methods, such as ozonolysis of vinyl ether in the presence of

imines,¹⁰¹ozonolysis of alkenes in the presence of primary

amines,¹⁰²and ozonolysis of the O-methylated diox-

imes.^103−105In all cases, 1,2,4-dioxazolidines were obtained,

at best, in moderate yields, and ozone, a toxic gas that has to be

generated on demand, was required. 1,2,4-Dioxazolidines can

also be prepared by oxidation of aziridines with singlet oxygen,

but in a low yield.^106−108One should also note the more recent

approaches to the synthesis of 8- and 11-membered cyclic

aminoperoxides via opening/recyclization of pentaoxaspiroal-

kanes with arylamines,¹⁰⁹condensation of pentane-1,5-dial

with gem-bis-hydroperoxides and primary amines,¹¹⁰and

interaction of heptaoxaspiroalkanes with diamines.¹¹⁰How-

ever, the need to start with the less accessible cyclic bis- or

trisperoxides signiﬁcantly limits the scope of the products.

Selective synthesis of azaperoxides from diketones remains a

challenge. For example, literature reports indicate that

synthesis of cyclic aminoperoxide from a diketone (hexane-

2,5-dione) was not possible due to steric reasons.⁹⁹Also, the

condensation of diketones with hydrogen peroxide and

ammonia can lead to the formation of a complex mixture of

products, both peroxide and non-peroxide in nature.

Condensation of 1,5-diketone 1l with 34% aqueous H₂O₂

and 22% aqueous NH₃in MeOH at a molar ratio 1,5-diketone

1l:H₂O₂:NH₃= 1:1.5:10 led to the formation of bridged

azaozonides in 84% yield with the ratio 2l:3l = 71:29 after 5 h

(run 1, Table 1). The yield of 2l + 3l and molar ratio 2l:3l

1

were determined from the H NMR data. In DMF and THF,

the azaozonides 2l + 3l were obtained in 54% and 60% yields,

respectively, in ∼40:60 2l:3l ratios (runs 2 and 3, Table 1).

With acetonitrile (run 4), azaozonides were not observed.

Under these conditions, acetonitrile was converted to

acetamide faster than the aminoperoxide was formed. The

optimal molar ratio for the condensation of 1,5-diketone 1l

with H₂O₂and NH₃was found to be 1l:H₂O₂:NH₃= 1:1.5:5,

and the reaction was complete in 1.5 h (run 5; for additional

experiments see Table S1 in the Supporting Information (SI)).

1

After ﬁnding the optimal conditions, we used H NMR to

monitor the formation of azaozonides 2l and 3l from 1,5-

diketone 1l, H₂O₂(aq), and NH₃(aq) in CD₃OD at 25 °C for

36 h (¹H NMR monitoring is presented in the SI). We found

that azaozonide 3l is a product of kinetic control, and

azaozonide 2l is a product of thermodynamic control. Also, ¹H

NMR monitoring demonstrated that 1.5 h after the start of the

reaction, the 2l:3l ratio was 37:63 (see the SI). However, the

2l:3l ratio changed to 87:13 after the reaction workup that

included removal of the solvent, excess of ammonia, and H₂O₂

(run 5 of Table 1). Taking into account these results, we

Furthermore, even though little is known about the

chemistry of aminoperoxides, there are indications that they

are capable of useful transformations. For example, it was

found that substituted 1,2,4-dioxazolidines are convenient

starting substrates for the synthesis of caprolactam and 11-

cyanoundecanoic acid as a precursor for polymer Nylon-12.¹¹¹

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Scheme 1. Structures and Isolated Yields of the Isomeric Mixtures of Azaozonides 2a−r and 3a−r, Synthesized from 1,5-

a

Diketones 1a−r

a

b

c

In brackets the time of the reaction. The ratio of 2a−r:3a−r is the average of three experiments. Under conditions of run 5, Table 1. Under

d

e

f

g

conditions of run 6, Table 1. Under conditions of run 7, Table 1. Under conditions of run 8, Table 1. Under conditions of run 9, Table 1. Scaled

to 1.0 g of 1,5-diketone 1 in the conditions of run 7, Table 1.

decided to change the procedure for the isolation of

azaperoxides from the reaction mixture. The extraction of

azaozonides directly from the reaction mixture with CHCl₃

allowed us to obtain the target azaozonides 2l + 3l in a 94%

yield and 33:67 ratio (run 6, Table 1).

azaperoxides from ammonium salts. These salts are more

convenient for dosing and using than NH₃(aq). By using

NH₄OAc and (NH₄)₂CO₃, azaozonides 2l + 3l were obtained

in 83% and 88% isolated yields, respectively (runs 7 and 9,

Table 1). With (NH₄)₂CO_3,the full conversion of diketone 1l

was achieved in 3 h, rather than 1.5 h for NH₄OAc. In the case

of ammonium formate, azaozonides 2l + 3l were obtained in

85% isolated yield in a ratio 2l:3l = 75:25 (run 8). With

(NH₄)₂SO₄, the target azaozonides were obtained only in trace

amounts. The conditions of entry 7 of Table 1 were chosen as

optimal when using ammonium salts as the NH source.

In the next step, we applied the optimized conditions to

explore the scope and limitations of the assembly of

azaozonides by introducing substituents R¹−R⁴at diﬀerent

positions in the 1,5-dicarbonyl compound 1. Azaozonides 2a−

r and 3a−r with various substituents were synthesized from

1,5-diketones 1a−r (Scheme 1). The NH₄OAc-promoted

reaction was monitored by TLC until complete conversion of

the starting 1,5-diketones 1a−r. Under conditions 7 of Table1,

the three-component condensations of 1.0 g of 1,5-diketone 1

formed azaperoxides 2b + 3b, 2c + 3c, 2d + 3d, 2f + 3f, 2h +

3h, and 2l + 3l in isolated yields of 93%, 88%, 94%, 78%, 80%,

and 86%, respectively. Although the diastereoisomeric bridged

However, isolation of the individual azaozonides from the

reaction mixture was not entirely trivial. The usual SiO₂

column chromatography with PE/EA as an eluent (run 5)

provided azaozonides 2l + 3l in only 66% yields with the ratio

2l:3l = 95:5. The 30% loss in the isolated yield in comparison

with the NMR yield suggested that azaozonide 3l may be more

sensitive to the acidic nature of SiO₂and degrades

preferentially relative to azaozonide 2l during column

chromatography (see the Computational Analysis section for

additional details). However, using 1 vol % Et₃N in CHCl₃as

eluent allowed us to isolate 2l + 3l in 83−88% yields without

signiﬁcant changes in the ratio 2l:3l in comparison with the ¹H

NMR of the reaction mixtures (runs 5−9).

Surprisingly, not only NH₃(aq), but also the ammonium

salts, such as ammonium acetate, ammonium formate, and

ammonium carbonate, can be used as an NH-group source in

the three-component condensation of 1,5-diketone 1l. To our

knowledge, there are no literature examples of the synthesis of

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Table 1. Synthesis of Stereoisomeric Bridged Azaozonides 2l and 3l via Condensation of 1,5-Diketone 1l with H₂O₂and an

a

NH-Group Source

run

NH-group source (equiv vs 1l)

solvent

time, h

NMR yield of 2l + 3l, % (isolated yield)

ratio of 2l:3l

1

2

3

4

5

NH₃aq (10)

NH₃aq (5)

MeOH

DMF

THF

CH₃CN

MeOH

5

84

54

60

71:29

39:61

37:63

1.5

94

(66)

(88)

94

(88)

95

(83)

94

87:13

95:5

92:8

d

e

b

6

NH₃aq (5)

MeOH

1.5

3

33:67

34:66

52:48

75:25

36:64

34:66

e

c

7

NH₄OAc (5)

HCOONH₄(5)

(NH₄)₂CO₃(5)

e

c

8

e

(85)

95

(88)

c

9

e

a

22% NH₃(aq) (0.39−0.77 mL, 4.60−9.20 mmol, 5−10 mol of NH₃/1 mol of 1l), NH₄OAc (0.355 g; 4.60 mmol), HCOONH₄(0.290 g; 4.60

mmol) or (NH₄)₂CO₃(0.442 g; 4.60 mmol), and 34% H₂O₂(aq) (0.12 mL, 1.38 mmol; 1.5 mol of H₂O₂/1 mol of 1l) were successively added

with stirring to a solution of 1,5-diketone 1l (0.300 g; 0.92 mmol) in MeOH, DMF, THF or CH₃CN (10 mL) at 20−25 °C. In the case of

(NH₄)₂CO₃, an additional 1 mL of H₂O was added to the reaction mixture. The reaction mixture was stirred at 20−25 °C for 1.5−5 h. The solvent,

excess of ammonia, and H₂O₂were removed in a vacuum of a membrane pump at 40−50 °C. The yields of 2l and 3l were determined from the ¹H

b

NMR spectroscopic data. Molar ratio 2l:3l is a mean from three experiments. The procedure for the isolation of azaozonides 2l + 3l from the

reaction mixture: CHCl₃(30 mL) and water (10 mL) were added to the reaction mixture. The organic phase was separated; the aqueous phase was

washed by CHCl₃(3 × 30 mL). The combined organic phases were dried over MgSO₄and ﬁltered. The solvent was removed in the vacuum of a

c

membrane pump at 20−25 °C. The yield of 2l and 3l was determined from the ¹H NMR spectroscopic data. The procedure for the isolation of

azaozonides 2l + 3l from the reaction mixture: CHCl₃(30 mL) and NaOH (5% aqueous solution, 10 mL) were added to the reaction mixture. For

d

e

the next steps see footnote b. The mixture of azaozonides 2l and 3l was isolated by chromatography on SiO₂using PE:EA = 20:1. The mixture of

azaozonides 2l and 3l was isolated by chromatography on SiO₂using 1% Et₃N in CHCl₃.

azaozonides 2a−r and 3a−r could not be separated using

conditions that worked for structurally similar diastereoiso-

meric bridged ozonides,^21,26,56we were able to separate

azaozonides 2m + 3m by ordinary column chromatography.

The structure and stereochemistry of peroxides 2m and 3m

were unambiguously established by X-ray crystallography. Both

azaozonides are crystalline compounds that melt without

decomposition at 136−138 °C and 120−122 °C, respectively.

An interesting result was obtained with the aminoperoxidation

of diketones 1s−v that have a single substituent at the tether

connecting the two ketone groups (Scheme 2). Under the

conditions of entry 7, Table 1, the reaction was carried out

until complete conversion of the starting 1,5-diketones 1s−v.

In the case of diketone 1v, we obtained a complex mixture of

products. The presence of the ester group in the α position of

the diketone 1v promotes its enolization, which probably

contributes to the formation of the dihydropyridine ring rather

than an aminoperoxide. According to NMR data, dihydropyr-

idine A and pyridine B were in the mixture, while the target

azaperoxide 2u was absent. However, azaozonides 2s−u were

obtained in 37−78% isolated yields from diketones 1s−u

(Scheme 2). The structure of 2t was unambiguously

established by X-ray crystallographic analysis.

Scheme 2. Attempted Peroxidative Condensations of 1,5-

Diketones 1s−v in the Presence of NH₄OAc

Stereochemical analysis of azaozonides 2a−r and 3a−r was

1

performed based on the ¹⁵N and key H chemical shifts in

combination with NOE data. For 2-CO₂R-substituted

azaozonides 2a−r and 3a−r, both diastereomers have

characteristic ¹⁵N chemical shifts (Figure 2, A) that makes

them easy to distinguish by conventional ¹H−¹⁵N HSQC

experiments. Also, the stereoisomer 3 has a characteristic signal

1

of one proton of the CH₂group in the H NMR spectra; its

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of X-ray data for 2m, 3m, and 2t is provided in the SI. An

interesting feature of the amino group is that it is strongly

pyramidalized in the direction that positions the lone pair of

nitrogen antiperiplanar to the two C−O bonds of the peroxide

ring. In the N-containing six-membered ring, the two C−O

bonds to the peroxide moiety are axial, as expected from the

generalized anomeric eﬀect.^113−116

Rearrangement of Bridged 1,2,4-Dioxazolidines

(Bridged Azaozonides). Due to the high energy of

peroxides, this functionality is prone to rearrangements.

Because the O−O bond is generally the “weakest link” in the

molecule, most of peroxide rearrangements proceed via O−O

bond scission, as illustrated by Baeyer−Villiger, Criegee,

Udris−Sergeev, Hock, Kornblum−DeLaMare, Wieland, and

Story reactions.¹²²Rearrangement of peroxides with preserva-

tion of the peroxide group is very rare. In fact, in the 100+

years of peroxide chemistry, only three such rearrangements

are known, namely, the Schenck rearrangement,^117,118the

Smith rearrangement,¹¹⁹and an interconversion of stereo-

isomeric ozonides and tricyclic monoperoxides (Scheme 3)

1

Figure 2. Basic H, ¹⁵N, and NOE NMR data for the stereochemical

analysis of main types of the synthesized azaozonides 2a−u and 3a−r.

proton falls into the anisotropy cone of the CO group and

has a chemical shift (2.5−2.7 ppm) (Figure 2, A). The

conﬁguration of a single diastereomer of the 2-aryl-substituted

azaozonides 2s−u was established using ¹H−¹H NOESY

spectra (Figure 2, B). The correctness of the performed

Scheme 3. Currently Known Rearrangements of Peroxides

That Preserve the Peroxide Group

assignments based on H and ¹⁵N chemical shifts was veriﬁed

1

by a number of NOE data. NMR analysis of azaozonides was

also facilitated by 2D correlation spectroscopic techniques

(COSY, NOESY, editing-HSQC, and HMBC) that were

previously calibrated by the NMR analysis of reference

ozonides.

Interestingly, the ¹⁵N NMR chemical shifts for the

aminoperoxides are quite diﬀerent from the chemical shifts

for amines (49.6 and 39.1 ppm for diethylamine and

piperidine, respectively; for the ¹⁵N NMR spectra for amines

see the SI) and are much closer to amides (106.4−108.4 and

102.2−104.2 ppm for N-methylformamide and N-methylace-

tamide, respectively¹¹²).

The NMR assignments were further conﬁrmed by X-ray

single-crystal analysis (Figure 3). A more detailed description

recently discovered by us.¹²⁰Such “peroxide-conserving”

rearrangements are exceptionally interesting from the

fundamental point of view because they reveal kinetically

favored reaction pathways far away from the thermodynamic

minima. Generally, such pathways navigate the “high-altitude”

regions of the potential energy surface and avoid falling down

to the lowest energy “thermodynamic bottom”. Such precise

navigation is generally made possible by using stereoelectroni-

cally assisted activation that can selectively break the usually

stronger (e.g., C−O) bonds in the presence of fragile O−O

groups.

Figure 3. Molecular structures of 2l, 2m, 3m, and 2t. Atoms are

presented as atomic displacement parameters (ADP) ellipsoids (50%

probability).

Our work describes the first peroxide-preserving rearrangement

of aminoperoxides in the history of peroxide chemistry.

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¹H NMR monitoring of the condensation of 1l with H₂O₂

and aqueous NH₃in CD₃OD demonstrated that the kinetically

preferable azaozonide 3l is thermodynamically less stable than

its isomer 2l (¹H NMR monitoring is presented in the SI). To

conﬁrm that azaozonides 3 can be rearranged into 2, a 22%

aqueous solution of NH₃and 34% aqueous solution of H₂O₂

were added (in the same amounts as in run 6 of Table 1) to a

solution of the mixtures of azaozonides 2h + 3h, 2k + 3k, or 2l

+ 3l in MeOH. The reaction mixtures were kept without

stirring for 24 h at 20−25 °C. After that, the ratio of

azaozonides 2h:3h changed from 70:30 to 91:9, for 2k:3k from

67:33 to 92:8, and for 2l:3l from 35:65 to 96:4 (Scheme 4).

conceptually important feature of these reactions is that they

represent the ﬁrst transformations of azaperoxides that

preserve the azaperoxide cycle (Scheme 5).

Scheme 5. Transformations of Azaperoxides 2h+3h with

Preservation of the Peroxide Cycle

Scheme 4. Rearrangement of Azaozonides 3 into

Azaozonides 2

In the case of azaozonides 2l + 3l, colorless crystals of 2l

were formed. The X-ray structure of 2l is shown in Figure 3.

Also, the rearrangement of 3 into 2 can be realized by

removing excess ammonia, hydrogen peroxide, and solvent on

a rotary evaporator under vacuum of a membrane pump at

40−50 °C (under conditions of high concentrations of

NH₃(aq) and H₂O₂(aq)). See the Computational Analysis

section below for a probable mechanism of this rearrangement.

Stability of Bridged 1,2,4-Dioxazolidines (Bridged

Azaozonides). All synthesized azaozonides 2a−u and 3a−r

are stable compounds and can be stored at room temperature

for several months without decomposition.

A pair of azaozonides 2l and 3l was used to study the

stability of azaozonides with respect to 98% H₂SO₄, KOH,

NH₃(aq), and NH₄OAc by NMR monitoring in CD₃OD with

1,4-dinitrobenzene as an internal standard (NMR spectra are

presented in the SI). Azaozonides 2l and 3l were unstable

toward H₂SO₄(5 μL of 98% H₂SO₄in 0.7 mL of CD₃OD per

50.0 mg of 2l + 3l). In 20 min after the addition of acid to the

mixture of 2l + 3l, the decomposition of azaozonides 2l and 3l

was observed (the content of azaozonides decreased by 42%

1

and 89%, respectively), and after 24 h, the H NMR signals

characteristic of azaozonides disappeared. As a result, a

complex mixture of products was formed where the initial

diketone 1l was also not detected. In the case of KOH, a

decrease in the amount of azaozonides 2l and 3l was observed

in 5 min after the KOH addition (by 12% and 17%,

respectively). After 24 h, a further decrease in the amount of

azaozonide 2l was not observed while the amount of

azaozonide 3l decreased by 67% from the initial. Furthermore,

azaozonide 2l was resistant to NH₃(aq) and NH₄OAc. In

contrast, azaozonide 3l was found to be sensitive NH₃(aq) but

less than that to NH₄OAc. In the case of NH₃(aq), the amount

of azaozonide 3l decreased by 35%, and in the case of

NH₄OAc, by 70% from the initial after 24 h. Thus, azaozonide

2l is resistant to KOH, NH₃(aq), and NH₄OAc and not

resistant to H₂SO₄. Azaozonide 3l is moderately resistant to

NH₃(aq) but not resistant to H₂SO₄, KOH, and NH₄OAc.

The unusual stability of bridged azaperoxides under basic

conditions opens the door for their modiﬁcations. A

In particular, acid 4 formed from azaperoxides 2h+3h can be

used to prepare amides 5 and 6. Note that the amine group in

2/3 does not react with the chloroformate. This is an unusual

behavior for an unprotected secondary amine. Although

isolation of azido-azaperoxide 6 is impractical, it can be used

“as prepared” in a noncatalyzed click reaction with the

formation of triazole-azaozonide 7 in 28% yield in two steps.

The electronically activated¹²¹cycloalkyne partner for this

reaction was synthesized according to the procedure of Harris

et al.¹²²in 55% yield.

COMPUTATIONAL ANALYSIS

■

All quantum chemical calculations were performed with the

Gaussian16¹²³program package at the PBE0¹²⁴-D3BJ¹²⁵/6-

311++G(d,p)^126−129/SMD¹³⁰(MeOH) level of theory. The

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PBE0 functional is known to provide accurate results for

organic reactions¹³¹and has been recently shown to be well

grounded in theory.^132−134All computational results are based

on quasi-harmonically corrected free energies computed with

GoodVibes.¹²⁶Monte Carlo conformational search was

performed for every computed intermediate and transition

state; in the latter case the forming and breaking bonds were

constrained at their lengths in a trial TS.¹³⁵Stereoelectronic

interactions were analyzed using natural bond orbital (NBO)

analysis.¹³⁶All energies are reported in kcal/mol.

Scheme 8. Proposed Mechanism for the Assembly and

Rearrangement of Aminoperoxides 2 and 3

a

Reaction Mechanism. To understand the mechanism of

aminoperoxide formation from 1,5-diketones, we have

modeled a variety of possible reaction pathways satisfying

the experimental observations. For example, we have

considered a route including the bicyclic ozonide (a close

analogue of azaozonide obtained from the same ketones under

acidic conditions and in the absence of NH₃^56,57) as an

intermediate. The negative Gibbs free energy for the

transformation of ozonide to aminoperoxide demonstrates

that this process is favorable thermodynamically (Scheme 6).

Hence, the ozonide is a plausible intermediate in the assembly

of the corresponding bicyclic aminoperoxide.

Scheme 6. Computed Free Energy of Transformation 15 →

3l in Reaction Media

a

All energies are reported in kcal/mol.

We have tested this scenario experimentally by introducing

ozonide 15 into the reaction conditions of entry 11, Table 1

(Scheme 7). Formation of aminoperoxides 2l and 3l was not

from 9x upon OH-group protonation, and then the resulting

imine 10x proceeds to nucleophilic addition of the H₂O₂

molecule from one of two sides. In order to close the second

cycle, the formed intermediate (11x or 13x) has to eliminate

the remaining OH group, leading to an imine (12x or 14x)

that ﬁnally undergoes intramolecular nucleophilic attack of the

imine carbon atom by the OOH group, resulting in the

aminoperoxide 2 or 3.

Scheme 7. Attempt to Synthesize Aminoperoxides from

Ozonides

The computational analysis also oﬀers a plausible mecha-

nism for the observed rearrangement of aminoperoxides

(Scheme 8). Alternative rearrangement mechanisms (see SI),

which do not require H₂O₂elimination, were found to be 3−5

kcal/mol higher in energy.

observed, and the ozonide remained unreacted. Thus, the

kinetic barrier for the transformation 15 → 3 is too high to

allow ozonides to be intermediates in the aminoperoxide

formation under these experimental conditions.

Modeling of the remaining reaction pathways for the

formation of aminoperoxides (see SI) was performed using

compound 1x, a simpliﬁed version of 1a with the CO₂Et group

replaced with CO₂Me to decrease conformational ﬂexibility.

Analysis of the thermodynamic landscape involved interaction

of the two nucleophiles (NH₃and H₂O₂) with the two

electrophilic centers of the diketone. The full network of

possibilities (six distinct paths with 18 intermediates) is shown

in the SI. The computationally favored path led us to the

aminoperoxidation mechanism shown in Scheme 8. The

reaction begins with nucleophilic addition of ammonia to a

β-carbonyl group of the starting 1,5-diketone 1x. Then it

follows an intramolecular nucleophilic addition of the NH₂

group to the carbonyl group in intermediate 8x, producing

cyclic intermediate 9x. This molecule undergoes a series of

elimination/addition steps: ﬁrst, a water molecule is eliminated

Transitions 10x → 13x and 10x → 11x have nearly identical

barriers (8.7 and 8.8 kcal/mol). If the subsequent exergonic

unimolecular steps in the parallel paths 10x → 2x and 10x →

3x are faster, one can expect that aminoperoxides 2x and 3x are

formed in a 47:53 ratio (according to the Curtin−

Hammett^137,138equation at 25 °C), resulting in a system

signiﬁcantly shifted from the equilibrium 78:22 ratio (energy

diﬀerence of 0.7 kcal/mol). This discrepancy between the

kinetic and equilibrium ratios gives rise to the observed

rearrangement. Since kinetic aminoperoxide 3x is 11.2 kcal/

mol more stable than 10x, the energy barrier of rearrangement

3x → 2x is 11.2 kcal/mol higher than the barrier of 10x → 2x

(i.e., 8.8 + 11.2 = 20.0 kcal/mol). This makes equilibration of

the 2x−3x mixture much slower than formation of amino-

peroxides from the starting 1,5-diketone 1x, in complete

agreement with the experimental results: conversion of the

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starting diketone into the initial mixture of 2l and 3l takes 1.5

h, while equilibrium is reached only after 36 h (see the SI).

It is also interesting to compare experimental equilibrium

ratios 2a:3a and 2l:3l with the computed ones, 2x:3x and 2l:3l,

under the assumption that the structural diﬀerence between 2a

and 2x in a single CH₂group does not inﬂuence selectivity

signiﬁcantly. The comparison in Scheme 9 shows surprisingly

good correspondence between experimental and computa-

tional data.

Scheme 9. Experimental and Computational Equilibrium

Ratios for Compounds 2 and 3

Figure 4. NBO analysis of aminoperoxides. Note that for this ﬁgure

geometry optimizations and NBO calculations were performed using

a larger, aug-cc-pVTZ¹³⁹basis (see Figure S5 for more information).

prevents them from taking the full advantage of the nitrogen

lone pair donor ability. As a reference point, it is instructive to

compare the bicyclic azaozonides with hexamethylene

triperoxide diamine,¹⁴⁰one of the few known compounds

containing geminal amine and peroxide groups. The latter

compound has a remarkable molecular geometry (Figure 5)

Stability and Electronic Structure of Bicyclic Azaozo-

nides. Intrigued by the high stability and unusual features of

these aminoperoxides, we have further explored their

electronic structure. An isodesmic reaction constructed to

highlight the diﬀerence between NH and O as neighbors for

the peroxide group (Scheme 10) shows that NH is preferred

Scheme 10. Isodesmic Reaction Identiﬁes the Amine Group

as the Preferred Neighbor for the Peroxide Group

by 5 kcal/mol. The likely origin of this stability is the stronger

anomeric interactions between the nitrogen lone pair and the

C−O antibonding orbital.

Figure 5. NBO analysis of hexamethylene triperoxide diamine

optimized at the PBE0-D3BJ/6-311++G(d,p)/SMD(MeOH) level

of theory.

Indeed, NBO analysis of a model aminoperoxide (Figure 4)

shows that each of the above-mentioned n_N→σ*_C−O

interactions amounts to 12.2 kcal/mol, while its n_O→σ*_C−O

analogue in ozonides is only 9.1 kcal/mol.⁵⁷In addition,

moderate n_O→σ*_C−Ninteraction amounts to 2.9 kcal/mol, a

little less than the corresponding n_O→σ*_C−Ointeraction in

ozonides (3.4 kcal/mol⁵⁷). Together, the anomeric inter-

actions in an aminoperoxide add up to 37.6 kcal/mol vs 25

kcal/mol in ozonides.⁵⁷Note that this diﬀerence in anomeric

stabilization (12.6 kcal/mol) closely matches the overall energy

diﬀerence between these compounds (11.4 kcal/mol, Scheme

6), highlighting the important role of hyperconjugative

interactions in the stability of aminoperoxides.

where the amino groups are nearly planar, in contrast to the

pyramidalized amino groups typical for amines.¹⁴¹Generally,

the cost of planarization in amines is paid by the greater donor

ability of nitrogen’s pure-p lone pairs in delocalizing

interactions.^142−144In hexamethylene triperoxide diamine,

the lone pair participates in three much stronger n_N→σ*_C−O

interactions (18.9 kcal/mol each, according to the NBO

analysis). In our aminoperoxides, however, NBO analysis of

the model compound found that planarization slightly weakens

(by <1 kcal/mol) both the n_N→σ*_C−Oand the n_O→σ*_C−N

interactions (see Figure S5 for details) by misaligning the

interacting orbitals. In the absence of greater delocalizing

stabilization, the cost of planarization (9.9 kcal/mol) remains

However, it is also clear that the bicyclic structure of our

aminoperoxides constrains their geometry in a way that

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about the same as in trimethylamine.¹⁴⁵From a practical

perspective, this analysis suggests that it should be possible to

design even more anomerically deactivated amines by the

future structural modiﬁcations.

+

Scheme 12. Computed Energies of Protonation by NH₄

and Deprotonation by NH₃in Reaction Media

More useful information from the NBO interaction energies

is that the n_N→σ*_C−Ointeractions are considerably stronger

than the n_O→σ*_C−Ninteractions (12.2 vs 2.9 × 2 kcal/mol).

This situation indicates a relatively unbalanced pattern of

delocalization where the nitrogen atom serves as a net donor

toward the two peroxide oxygens. The imbalance is

considerably more pronounced than in the case of the

analogously coupled n_N→σ*_C−O/n_O→σ*_C−Ninteractions in a

hemiaminal (i.e., NR₂CH₂OR). It partially stems from the

decreased donor ability of peroxide lone pairs (“the inverse α-

eﬀect”¹¹⁶) that we have identiﬁed recently as an important

factor in peroxide chemistry.^146−150

In order to further understand the interplay of structure and

reactivity for the aminoperoxides 2l and 3l, the chemical

properties of their NH groups were studied computationally in

diﬀerent roles, i.e., as bases, acids, and nucleophiles.

The nucleophilicity of 2l was evaluated by comparing the

activation barriers of its S_N2 reaction with methyl chloride with

those for 2l_C (its analogue with the peroxide fragment

replaced with a CH₂−CH₂group) and dimethylamine (see

Scheme 11). The neighboring peroxide fragment increases the

the penalty associated with the loss of n_N→σ*_C−Ointeraction

upon protonation.

Furthermore, the computed deprotonation energies show

opposite trends in acidity, which illustrates the ability of the

vicinal peroxide group to stabilize the negative charge on the

nitrogen. Thus, the presence of vicinal peroxide deactivates the

NH group’s lone pair but simultaneously increases the N−H

acidity.

The strong stereoelectronic interactions manifest themselves

not only in reactivity but also in the NMR spectra. In the case

of azaozonides, n_N→σ*_C−Odelocalization deshields the

nitrogen atom, and, therefore, its ¹⁵N NMR peak is expected

to be shifted downﬁeld. In order to estimate this deshielding,

¹⁵N chemical shifts of 2l, 2l_C, and 2l′ (conformation of 2l′

with the N−H bond parallel to C−O) were computed using

the GIAO method (see Scheme 13). According to calculations,

Scheme 11. Activation Energies of S_N2 Reaction with

Methyl Chloride Reveal Decreased Nucleophilicity of the

Nitrogen Atom in Aminoperoxides

Scheme 13. ¹⁵N Chemical Shifts Computed Using the GIAO

Method at the PBE0-D3BJ/6-311++G(d,p)/SMD(CHCl₃)

a

Level of Theory

a

Calculated chemical shift of NH₃was used as the standard.

the nitrogen signal of 2l is shifted downﬁeld by 14−18 ppm

away from the peaks of 2l_C and 2l’, where the n_N→σ*_C−O

hyperconjugation is “turned oﬀ ”. So, this interaction is indeed

responsible for the deshielding of the nitrogen atom, and the

unusual ¹⁵N NMR chemical shifts in azaozonides can be taken

as spectroscopic signatures of such stereoelectronic eﬀects.

Another interesting feature of azaozonide reactivity is the

diﬀerence between rates of 2l and 3l degradation in acidic

media. Lower stability of 3l against H₂SO₄and SiO₂was

observed experimentally and was already mentioned in the

synthetic section. Our calculations show that this diﬀerence

comes from the closeness of peroxide oxygen to the ester side-

group in 3l. Computational analysis of protonated azaozonide

3l·H⁺and the corresponding TS reveals that the protonated

ester group of 3l acts as a proton donor for the peroxide group

in the TS for C−O scission, thus stabilizing it and promoting

the ring opening (Scheme 14).

activation energy by 6−7 kcal/mol (2l vs 2l_C), while

embedding the NH group in the strained bicyclic system

increases that by an additional 2−4 kcal/mol (2l_C vs

dimethylamine). The latter observation can be traced to the

increase of the nitrogen lone pair s-character caused by its

strain-induced rehybridization in the polycyclic framework.¹⁴¹

Together, these computational results agree with the

experimentally observed inactivity of aminoperoxides 2−3l

toward alkylation with alkyl halides and acylation with acetyl

chloride or acetic anhydride.

Trends in basicity (see Scheme 12) correlate with activation

energies of S_N2 reactions and reveal another manifestation of

the strong n_N→σ*_C−Ointeraction in aminoperoxides. Proto-

nation energies of aminoperoxides 2l and 3l are ∼18.5 kcal/

mol higher than those for corresponding amines 2l_C and

3l_C. Thus, the peroxide group makes aminoperoxides less

basic by ∼15 pK_bunits! This extremely large eﬀect comes from

The unusual behavior of the NH group in aminoperoxides

can be useful for the medicinal chemistry of peroxides, since its

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obtained free of charge via www.ccdc.cam.ac.uk/data_request/

cif, or by emailing data_request@ccdc.cam.ac.uk, or by

contacting The Cambridge Crystallographic Data Centre, 12

Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Scheme 14. Ring-Opening Activation Energies of Neutral

and Protonated Forms of 3l in kcal/mol

AUTHOR INFORMATION

■

Corresponding Authors

Ivan A. Yaremenko − N. D. Zelinsky Institute of Organic

Chemistry, Russian Academy of Sciences, 119991 Moscow,

Russian Federation; orcid.org/0000-0003-1068-9051;

Email: yaremenko@ioc.ac.ru

Alexander O. Terent’ev − N. D. Zelinsky Institute of Organic

Chemistry, Russian Academy of Sciences, 119991 Moscow,

Russian Federation; orcid.org/0000-0001-8018-031X;

Email: terentev@ioc.ac.ru

Igor V. Alabugin − Department of Chemistry and

Biochemistry, Florida State University, Tallahassee, Florida

32306, United States; orcid.org/0000-0001-9289-3819;

Email: alabugin@chem.fsu.edu

NH group does not interact with alkylating agents but can act

as a strong H-bond donor when interacting with biosystems.

CONCLUSION

■

Stable bridged azaozonides are assembled via a catalyst-free

three-component condensation of 1,5-diketones with hydrogen

peroxide and an NH-group source such as aqueous ammonia,

ammonium acetate, formate, or carbonate. This approach

opens synthetic access to bridged azaozonides with various

functional groups such as alkene, alkyne, ester, and cyano. The

synthesis is readily scalable and opens practical access to gram

quantities of the target azaozonides. The azaozonides can be

stored at room temperature for several months without

decomposition. They were isolated by ordinary column

chromatography and fully characterized by NMR spectroscopy,

mass spectrometry, X-ray, and elemental analysis. The ﬁrst

rearrangement in the class of aminoperoxides with preservation

of the peroxide group was discovered. The stability of

azaozonides was examined under acidic and basic conditions.

The approach to azaozonides disclosed in this work makes this

ﬁeld of peroxide chemistry readily available for further

exploration.

Authors

Yulia Yu. Belyakova − N. D. Zelinsky Institute of Organic

Chemistry, Russian Academy of Sciences, 119991 Moscow,

Russian Federation

Peter S. Radulov − N. D. Zelinsky Institute of Organic

Chemistry, Russian Academy of Sciences, 119991 Moscow,

Russian Federation; orcid.org/0000-0003-2653-0395

Roman A. Novikov − N. D. Zelinsky Institute of Organic

Chemistry, Russian Academy of Sciences, 119991 Moscow,

Russian Federation; orcid.org/0000-0002-3740-7424

Michael G. Medvedev − N. D. Zelinsky Institute of Organic

Chemistry, Russian Academy of Sciences, 119991 Moscow,

Russian Federation; orcid.org/0000-0001-7070-4052

Nikolai V. Krivoshchapov − N. D. Zelinsky Institute of

Organic Chemistry, Russian Academy of Sciences, 119991

Moscow, Russian Federation

Alexander A. Korlyukov − A. N. Nesmeyanov Institute of

Organoelement Compounds, Russian Academy of Sciences,

119991 Moscow, Russian Federation; orcid.org/0000-

0002-5600-9886

Computational analysis reveals that n_N→σ*_C−Ohyper-

conjugation is the key factor making NH a more favorable

neighbor for the peroxide group than the oxygen atom, making

azaozonides thermodynamically preferable over ozonides. The

signiﬁcant imbalance in the magnitude of n_N→σ*_C−Oand n_O→

σ*_C−Ninteractions between the amino and the peroxide groups

is responsible for the unusually low basicity and nucleophilicity

of azaozonides. This imbalance is ampliﬁed by the inverse α-

eﬀect, an important factor in peroxide reactivity. A

combination of control experimental and computational

analysis identiﬁed plausible mechanisms of the assembly and

rearrangement of azaozonides. Interestingly, the two processes

include the same intermediates: the rearrangement is driven by

a diﬀerence in the kinetic and thermodynamic ratios of the

azaozonide diastereomers.

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.1c02249

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

A.O.T., I.A.Y., Y.Y.B., P.S.R., R.A.N., M.G.M., N.V.K., and

A.A.K. are grateful for the support of the Russian Science

Foundation (Grant No. 21-43-04417). Quantum chemical

calculations have been carried out using computing resources

of the federal collective usage center Complex for Simulation

and Data Processing for Mega-science Facilities at NRC

“Kurchatov Institute”, http://ckp.nrcki.ru/. The Siberian

Branch of the Russian Academy of Sciences (SB RAS)

Siberian Supercomputer Center is gratefully acknowledged for

providing supercomputer facilities. The research is carried out

using the equipment of the shared research facilities of HPC

computing resources at Lomonosov Moscow State Univer-

sity.¹⁵¹The authors acknowledge the computational resources

provided by the Moscow State University’s Faculty of

Computational Mathematics and Cybernetics (IBM Blue

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.1c02249.

■

sı

Experimental details, characterization data, and quantum

chemical calculations (PDF)

Computational data (XYZ)

Accession Codes

CCDC 2052452−2052454 and 2059164 contain the supple-

mentary crystallographic data for this paper. These data can be

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Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides

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